Vertical Pathway Inhibition Overcomes Adaptive Feedback Resistance to KRAS Inhibition.

Purpose: Although represents the most commonly mutated oncogene, it has long been considered an "undruggable" target. Novel covalent inhibitors selective for the KRAS mutation offer the unprecedented opportunity to target KRAS directly. However, prior efforts to target the RAS-MAPK pathway have been hampered by adaptive feedback, which drives pathway reactivation and resistance.

Experimental Design: A panel of cell lines were treated with the KRAS inhibitors ARS-1620 and AMG 510 to assess effects on signaling and viability. Isoform-specific pulldown of activated GTP-bound RAS was performed to evaluate effects on the activity of specific RAS isoforms over time following treatment. RTK inhibitors, SHP2 inhibitors, and MEK/ERK inhibitors were assessed in combination with KRAS inhibitors and as potential strategies to overcome resistance and enhance efficacy.

Results: We observed rapid adaptive RAS pathway feedback reactivation following KRAS inhibition in the majority of KRAS models, driven by RTK-mediated activation of wild-type RAS, which cannot be inhibited by G12C-specific inhibitors. Importantly, multiple RTKs can mediate feedback, with no single RTK appearing critical across all KRAS models. However, coinhibition of SHP2, which mediates signaling from multiple RTKs to RAS, abrogated feedback reactivation more universally, and combined KRAS/SHP2 inhibition drove sustained RAS pathway suppression and improved efficacy and .

Conclusions: These data identify feedback reactivation of wild-type RAS as a key mechanism of adaptive resistance to KRAS inhibitors and highlight the potential importance of vertical inhibition strategies to enhance the clinical efficacy of KRAS inhibitors..